Exploring the Use of Emergency Investigational New Drug Therapy in 3 Pediatric Patients with Inborn Errors of Metabolism
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Other Therapies
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Secondary Categories:
- Other Therapies
Introduction:
The rarity and heterogeneity of inborn errors of metabolism (IEM) and primary mitochondrial disease have historically eluded systematic clinical trials that may result in FDA approved disease modifying therapies. While this landscape is now shifting, and many clinical trials for genetic diseases are underway, the clinician is often faced with few treatment options when faced with life-threatening manifestations of IEMs due to a lack of approved therapies. Individual INDs can allow the clinician to offer an investigational product to patients and families in emergent or life-threatening circumstances, through swift evaluation and approval with the FDA. Safety profile, potential risks, and benefits are all weighed against the emergent nature of the clinical circumstances. This can serve as a tool for precision medicine, lead to improved clinical outcomes in otherwise dire clinical scenarios, and add to the totality of evidence when considering the efficacy of an investigational product in rare disease, where we are often stymied by small sample sizes in clinical trials. We present 3 pediatric cases where an eIND demonstrated clinical success in managing an untreatable, complex, and lethal IEM. Furthermore, we discuss the process and utility of using underutilized eINDs in the academic setting to improve patient outcomes in IEM.
Methods:
This is a case series that explores the use of eINDs at a large academic metabolic center to treat 3 pediatric patients with different IEMs between August 2021 and November 2024.
Results:
Case 1 is a male neonate with ECHS1 deficiency primary lactic acidosis, which has a mortality rate approaching 100%, who was treated with sodium dichloroacetate (DCA) and subsequent stabilization of his acid-base status, and eventual discharge home. He has survived past one year of age and is maintained on DCA therapy via eIND. Case 2 is a male neonate with Barth syndrome (TAFFAZIN) and associated severe fetal dilated noncompaction cardiomyopathy who was treated with elamipretide and had gradual improvement and eventual delisting from cardiac transplant. Finally, case 3 was a female infant with cardiomyopathy and hypotonia secondary to multiple acyl-CoA-dehydrogenase deficiency (MADD) type II due to a defect in ETFDH and was started on compounded ketone therapy which improved muscle strength and cardiac function.
Conclusion:
Acute decompensation in IEM has been challenging to manage and treat when there are limited available approved therapies. The FDA’s eIND expands treatment options by exploring novel therapies that can rapidly be trialed in critically ill patients. We presented 3 pediatric patients with life-threatening IEMs who received eIND therapy with favorable clinical outcomes. We advocate for the use of eINDs in rare diseases, particularly in the absence of approved disease targeting therapies and disorders with a high mortality rate.
The rarity and heterogeneity of inborn errors of metabolism (IEM) and primary mitochondrial disease have historically eluded systematic clinical trials that may result in FDA approved disease modifying therapies. While this landscape is now shifting, and many clinical trials for genetic diseases are underway, the clinician is often faced with few treatment options when faced with life-threatening manifestations of IEMs due to a lack of approved therapies. Individual INDs can allow the clinician to offer an investigational product to patients and families in emergent or life-threatening circumstances, through swift evaluation and approval with the FDA. Safety profile, potential risks, and benefits are all weighed against the emergent nature of the clinical circumstances. This can serve as a tool for precision medicine, lead to improved clinical outcomes in otherwise dire clinical scenarios, and add to the totality of evidence when considering the efficacy of an investigational product in rare disease, where we are often stymied by small sample sizes in clinical trials. We present 3 pediatric cases where an eIND demonstrated clinical success in managing an untreatable, complex, and lethal IEM. Furthermore, we discuss the process and utility of using underutilized eINDs in the academic setting to improve patient outcomes in IEM.
Methods:
This is a case series that explores the use of eINDs at a large academic metabolic center to treat 3 pediatric patients with different IEMs between August 2021 and November 2024.
Results:
Case 1 is a male neonate with ECHS1 deficiency primary lactic acidosis, which has a mortality rate approaching 100%, who was treated with sodium dichloroacetate (DCA) and subsequent stabilization of his acid-base status, and eventual discharge home. He has survived past one year of age and is maintained on DCA therapy via eIND. Case 2 is a male neonate with Barth syndrome (TAFFAZIN) and associated severe fetal dilated noncompaction cardiomyopathy who was treated with elamipretide and had gradual improvement and eventual delisting from cardiac transplant. Finally, case 3 was a female infant with cardiomyopathy and hypotonia secondary to multiple acyl-CoA-dehydrogenase deficiency (MADD) type II due to a defect in ETFDH and was started on compounded ketone therapy which improved muscle strength and cardiac function.
Conclusion:
Acute decompensation in IEM has been challenging to manage and treat when there are limited available approved therapies. The FDA’s eIND expands treatment options by exploring novel therapies that can rapidly be trialed in critically ill patients. We presented 3 pediatric patients with life-threatening IEMs who received eIND therapy with favorable clinical outcomes. We advocate for the use of eINDs in rare diseases, particularly in the absence of approved disease targeting therapies and disorders with a high mortality rate.